The addition of daratumumab (Darzalex) to bortezomib (Velcade), melphalan, and prednisone (VMP) reduced the risk of progression or death by 50% compared with VMP alone for transplant-ineligible patients with newly diagnosed multiple myeloma, according to findings from the phase III ALCYONE trial presented at the 2017 ASH Annual Meeting and simultaneously published in the New England Journal of Medicine.
At a median follow-up of 16.5 months, the 18-month progression-free survival (PFS) rate with the daratumumab-containing regimen was 71.6% (95% CI, 65.5%-76.8%) compared with 50.2% (95% CI, 43.2%-56.7%) for VMP alone (HR, 0.50; 95% CI, 0.38-0.65; P
<.001). There were marked improvements in response rates with the addition of the anti-CD38 monoclonal antibody; however, an increased rate of grade 3/4 infections was also observed.
"ALCYONE strongly supports D-VMP as a standard of care in transplant-ineligible newly-diagnosed multiple myeloma," lead investigator Maria-Victoria Mateos, MD, PhD, director of the Myeloma Unit at University Hospital of Salamanca-IBSAL Salamanca, Spain, said during a presentation of the results. "Daratumumab plus VMP reduced the risk of progression or death and induced significantly deeper responses. There were no new safety signals observed except for higher infection events that resolved."
In the open-label ALCYONE trial, 706 with newly diagnosed multiple myeloma were randomized to receive VMP alone (n = 356) or in combination with daratumumab (n = 350). Bortezomib was administered at 1.3 mg/m2
subcutaneously twice weekly in cycle 1 and once weekly for cycles 2 through 9. Melphalan was dose at 9 mg/m2
on days 1 to 4 and prednisone was administered at 60 mg/m2
on days 1 to 4. Daratumumab was added at 16 mg/kg once weekly in cycle 1 and every 3 weeks in cycles 2 through 9. Beyond month 9 in the investigational arm, daratumumab was continued every 4 weeks until disease progression.
Baseline characteristics were similar between the two groups of patients. In the daratumumab arm, the median age was 71 years and 30% were ≥75 years of age. The ECOG performance status was 0 (22%), 1 (52%), and 2 (26%). Ten percent of patients had light chain myeloma, with the remainder being IgG (64%) and IgA (21%). The most common ISS stages were III (41%) and II (40%). Seventeen percent of patients were high-risk by cytogenetic profile.
The median PFS was 18.1 months in the VPM arm and was not yet reached for those treated with the daratumumab regimen. At the 12-month assessment, 87% of patients remained alive and progression-free in the daratumumab group versus 76% for VMP. PFS was improved with the addition of daratumumab across subgroups.
The objective response rate (ORR) with the daratumumab regimen was 90.9% compared with 73.9% in the control arm (P <.001), this included a complete response (CR) or better for 42.6% of patients in the daratumumab arm compared with 24.4% in the VMP alone group (P <.001). The very good partial response or better rate was 71% for daratumumab versus 50% for VMP alone. The median duration of response was 21.3 months for VMP and was not yet reached in the daratumumab group.
Three-fold more patients tested negative for minimal residual disease (MRD) in the daratumumab group versus VMP alone. In the investigational arm, 22.3% were negative for MRD versus 6.2% in the VMP group (P
<.001). Regardless of the treatment used, those with MRD-negative disease had a lower risk of disease progression or death compared with MRD-positive patients, noted Mateos.
At the time of the analysis, there had been 45 deaths in the daratumumab group and 48 in the VMP arm. Eighty-seven percent of patients remained alive in both groups. Follow-up for long-term survival remains ongoing.
The most common hematologic adverse events (AEs) of grade 3/4 severity with the daratumumab combination versus VMP alone, respectively, were neutropenia (39.9% vs 38.7%), thrombocytopenia (37.6% vs 34.4%), and anemia (19.8% vs 15.9%). The most common grade 3/4 nonhematologic AEs for daratumumab versus VMP, respectively, were peripheral sensory neuropathy (1% vs 4%), diarrhea (3% each), and pneumonia (11% vs 4%). Infusion-related reactions occurred in 27.7% of patients in the daratumumab group.
The rate of grade 3/4 infection was 23.1% for daratumumab compared with 14.7% for VMP alone. Infections led to treatment discontinuation for 1.4% of patients in the VMP group and 0.9% in the daratumumab group.
"The treatment was very well tolerated. Infusion reactions occur during the first course and are usually grade 1 or 2," said senior study author Jesus F. San-Miguel, MD, medical director of the Clínica Universidad de Navarra in Pamplona, Spain. "A slightly higher incidence of infections and pneumonia were observed in the daratumumab arm, but few patients discontinued treatment and only 1 patient per arm discontinued due to pneumonia."
Serious adverse events occurred in 41.6% of patients in the daratumumab arm and for 32.5% of patients in the VMP group. AEs led to discontinuation for 4.9% of patients in the daratumumab group versus 9.0% for the control arm.
“Monoclonal antibodies like daratumumab have already been approved for use in relapsed patients; here, we are showing that the benefits extend to newly diagnosed patients, as well," said San-Miguel. "There are several additional frontline daratumumab studies ongoing in order to establish, for everyone, a new standard of care with a monoclonal antibody up front."
In November 2016, the FDA approved daratumumab in combination with lenalidomide (Revlimid) and dexamethasone or bortezomib and dexamethasone for patients with relapsed multiple myeloma following at least 1 prior therapy. Based on the ALCYONE data, a supplemental biologics license application was submitted to the FDA in November for daratumumab plus VMP for transplant-ineligible patients with newly diagnosed multiple myeloma.
- Mateos M-V, DA Meletios, Cavo M, et al. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N Engl J Med. 2017. DOI:10.1056/NEJMoa1714678.
- Mateos M-V, DA Meletios, Cavo M, et al. Phase 3 Randomized Study of Daratumumab Plus Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) in Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) Ineligible for Transplant (ALCYONE). Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta, Georgia. Abstract LBA-4.